PHYSIOLOGICAL SYNERGISM BETWEEN CONOTOXINS

在上一次授权期内，我们获得了猎物捕获的证据 猎鱼锥形蜗牛的策略涉及到组合使用 毒品战略。所有捕鱼的锥形蜗牛都会干扰神经肌肉 通过使用多个针对重要受体的多肽进行传播 以及马达电路(马达电缆)中的离子通道。然而，许多人 捕食圆锥体的鱼类显然也含有一系列毒素 在猎物中引起兴奋毒性休克的毒液，导致非常 快速、僵硬的瘫痪(雷击阴谋集团)。 两个猎鱼圆锥的雷击和马达阴谋 对紫锥虫和大圆锥虫的种类进行了详细的分析， 所涉及的每个圆锥体多肽的药理特异性将是 下定决心。我们的数据表明，单个多肽不仅存在分歧 在结构上，但如果比较两种毒液，可能针对不同的位置。 我们已经提供了初步证据表明，捕鱼的锥形蜗牛 使用网策略(而不是更常见的钩线方法 为了抓鱼)没有雷击阴谋，而是 在汽车集团面前对猎物产生麻醉和镇静样作用 作用于干扰神经肌肉传递。这一组多肽是 一般认为压抑的感觉系统属于 涅槃阴谋，这可能有助于捕获小鱼群的一个 一只蜗牛。涅槃阴谋集团特别感兴趣的是 Conantokins，亚型特异性NMDA受体拮抗剂，具有 最近被证明是有效的抗惊厥药物，具有很高的保护性 指数。因此，属于圆锥体的多肽的性质 涅槃阴谋可能会提供新的工具来抑制 神经系统。

In the last grant period, we obtained evidence that the prey-capture strategy of fish-hunting cone snails involves the use of a combination drug strategy. All fish hunting cone snails interfere with neuromuscular transmission by using multiple peptides which target important receptors and ion channels in the motor circuitry (the motor cabal). However, many fish hunting Conus species apparently also have a set of toxins in their venom which elicits excitotoxic shock in the prey, resulting in a very rapid, rigid paralysis (the lightning-strike cabal). The lightning-strike and motor cabals of two fish-hunting Conus species, Conus purpurascens and Conus magus will be analyzed in detail, and the pharmacological specificity of each Conus peptide involved will be determined. Our data suggest that individual peptides not only diverge structurally but may target different sites if two venoms are compared. We have presented preliminary evidence that fish-hunting cone snails that use a net strategy (instead of the more common hook-and-line method for catching fish) do not have the lightning-strike cabal, but instead elicit anesthetic and sedative-like effects in prey before the motor cabal acts to disrupt neuromuscular transmission. The group of peptides which generally suppress sensory systems are hypothesized to belong to the nirvana cabal, which may facilitate capture of small schools of fish by a single snail. Of exceptional interest within the nirvana cabal are the conantokins, subtype-specific NMDA receptor antagonists which have recently been shown to be potent anticonvulsants with a high protective index. Thus, the characterization of the Conus peptides which belong to the nirvana cabal may provide novel tools for suppressing the activity of the nervous system.